Macrophages play a major role in diseases such as tuberculosis, Leishmania, chronic inflammation, autoimmune diseases, atherosclerosis, obesity, asthma, fibrosis, and cancer, and the disease progression is strongly affected by whether the macrophages are inflammatory M1, profibrotic M2a, or immunoregulatory M2reg. The differentiation of monocytes into M1, M2a, or M2reg has been thought to occur in response to signals released during inflammation or repair. Unexpectedly, a constitutive blood plasma protein called Serum Amyloid P (SAP) induces monocytes to become M2reg macrophages. Signals inducing and produced by M2a macrophages are associated with fibrosis. Injections of SAP in animal models of fibrosis override these signals, induce M2reg differentiation, and inhibit fibrosis. These results suggest that SAP is a constitutive, and at high levels a dominant, regulatory signal in the innate immune system. SAP is a member of the pentraxin family that includes C-polysaccharide reactive protein (CRP) and pentraxin-3 (PTX3). Although CRP has strong sequence and structural similarity to SAP, CRP is a major marker of inflammation, but in some animal models CRP potentiates inflammation, and in other models CRP inhibits inflammation. In an effort to resolve this discrepancy, we found that CRP induces the differentiation of monocytes into Mreg, but induces macrophages to polarize into M1. To gain insight into a fundamental mechanism used to regulate the innate immune system, we propose three specific aims to elucidate the molecular mechanism used by pentraxins to regulate macrophage phenotype. Our first aim is to test the hypothesis that pentraxins can have different effects on macrophage differentiation compared to macrophage polarization, and test the hypothesis that ligands that bind pentraxins affect pentraxin signaling. Even though SAP, CRP, and PTX3 have distinct effects on macrophage phenotype, they all bind to Fc? receptors on cells. Our second aim is to distinguish between models where SAP activates some Fc? receptors and CRP (and/or PTX3) activates other Fc? receptors, and models where one or more of the pentraxins signals through other receptors to regulate macrophage phenotype. Our third aim is to determine the contribution of human Fc? receptors to pentraxin regulation of human macrophage phenotype. We will then use this information to screen for compounds that block the binding of a given pentraxin to a given Fc? receptor, and thus in the presence of the pentraxin, alter macrophage phenotype. Together, this work will help to elucidate a novel mechanism used by the innate immune system to regulate macrophage differentiation, and may lead to new therapies for macrophage-associated diseases.